The present invention relates to the production of a crystalline compound that is useful as a glucagon receptor antagonist. The compound is of the formula I:
It is useful for treating diabetes, especially type 2 diabetes, and related conditions.
During the production of pharmaceuticals, the formation of solids is most often accomplished by crystallization in the solution phase followed by isolation and drying. The dry active organic compound is typically further processed to reach a particle size profile that is optimal for formulation of the end product. The resultant particle size can vary significantly, in most cases, having a mean size less, than 300 μm.
The formation of a new solid phase by crystallization, from solute dissolved in liquid, is generally accepted to occur by the following pathway: (1) nucleation of new particles and (2) growth through deposition of solute on existing particles. Nucleation can occur on foreign substances in a crystallizer or homogeneously from solution. U.S. Pat. No. 5,314,506 entitled “Crystallization method to improve crystal structure and size” and U.S. Published Patent Application No. 2004/0091546 A1 entitled “Process and apparatuses for preparing nanoparticle compositions with amphiphilic copolymers and their use” describe small particles, even nanoparticles, produced by massive nucleation of many new particles of the solute during precipitation. In these processes, the character of the system is changed using solvent composition and temperature of reaction, to create high supersaturation for the solute which in turn leads to rapid nucleation and crystallization. The birth of many particles by nucleation leads to a small particle size distribution at the end of the crystallization step, thereby obviating the need for dry milling.
However, under supersaturation conditions, undesirable solid state forms, such as molecular packings in a crystal, can be produced. In addition, crystals with occluded solvent molecules or impurities, may be produced, requiring further purification.
In an effort to control the morphologic properties of the final product, it is desirable to use seed particles of the product to provide a template for crystal growth during crystallization. Seeding helps control the particle size, crystal form, and chemical purity. Various milling techniques have been employed to generate the seed stock. Dry milling has been used routinely to generate small particles for crystallization seed that result in particles of moderate size. This approach does not eliminate the previously discussed engineering and safety concerns associated with dry milling and is less desirable than a wet milling technique for seed generation.
Rotor-stator wet milling can be used to generate relatively large seed particles with a practical limit of greater than about 20 μm. On the other hand, milling to this size requires extended milling time in the attrition regime where small fragments lead to a bimodal particle size distribution (American Pharmaceutical Review Vol 7, Issue 5, pp 120-123, “Rotor Stator Milling of API's . . . ). It has been found that crystallizations using rotor-stator wet milled products as seed result in large particles and, most often, a bimodal particle size distribution. A subsequent dry milling step is required to create the desired small sized crystals or monomodal material.
Sonication is another technique for generating large seeds for crystallization. Sonication has been shown to yield product greater than about 100 μm (See U.S. Pat. No. 3,892,539 entitled “Process for production of crystals in fluidized bed crystallizers”).
Media milling has recently been used to create final product streams for direct formulation of pharmaceuticals with particulates less than about 400 μm (See U.S. Pat. No. 5,145,684). A review of media milling and its utilities is described in U.S. Pat. No. 6,634,576.
U.S. Pat. No. 3,804,653 relates to media that is formulated of sand, beads, cylinders, pellets, ceramic or plastic. The mill can be formulated of metal, steel alloy, ceramic and that the mill may be lined with ceramic. Plastic resin including polystyrene is noted as being particularly useful. U.S. Pat. No. 4,950,586 relates to the use of zirconium oxide beads to mill organic dyes to below 1μ in the presence of stabilizers. In one embodiment of the present invention, ceramic beads and a ceramic mill are utilized. In a further embodiment, ceramic beads and a chromium-lined mill are utilized.
In the present invention, wet milled micro-seed with a mean particle size ranging from about 0.1 to about 20 μm has been shown to be surprisingly effective for the production of particles of Formula I with a controlled particle size distribution, crystal form, and purity. Further advantages of the present invention include the elimination of the need for downstream dry milling, thereby eliminating the health and safety hazards often associated with these processes.